EP0030870A1 - Process for producing solutions of aziridine-2-carboxylic acid salt - Google Patents
Process for producing solutions of aziridine-2-carboxylic acid salt Download PDFInfo
- Publication number
- EP0030870A1 EP0030870A1 EP19800304566 EP80304566A EP0030870A1 EP 0030870 A1 EP0030870 A1 EP 0030870A1 EP 19800304566 EP19800304566 EP 19800304566 EP 80304566 A EP80304566 A EP 80304566A EP 0030870 A1 EP0030870 A1 EP 0030870A1
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- European Patent Office
- Prior art keywords
- alpha
- beta
- ester
- water
- metal hydroxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 35
- WBGBOXYJYPVLQJ-UHFFFAOYSA-N aziridine-2-carboxylic acid Chemical class OC(=O)C1CN1 WBGBOXYJYPVLQJ-UHFFFAOYSA-N 0.000 title claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 15
- 239000011707 mineral Substances 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 14
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 11
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims abstract description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- -1 isopropyl ester Chemical class 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical group [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims 2
- 125000004492 methyl ester group Chemical group 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 10
- ZGQWDLXRNCMIHH-UHFFFAOYSA-M lithium;aziridine-2-carboxylate Chemical compound [Li+].[O-]C(=O)C1CN1 ZGQWDLXRNCMIHH-UHFFFAOYSA-M 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- BUBYPUXPXVAVMY-UHFFFAOYSA-N 3-amino-2-chloropropanoic acid;hydrochloride Chemical compound Cl.NCC(Cl)C(O)=O BUBYPUXPXVAVMY-UHFFFAOYSA-N 0.000 description 7
- FJAWVRZITFCHEK-UHFFFAOYSA-M sodium;aziridine-2-carboxylate Chemical compound [Na+].[O-]C(=O)C1CN1 FJAWVRZITFCHEK-UHFFFAOYSA-M 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000004811 liquid chromatography Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XBQQNEFVNFNHDA-UHFFFAOYSA-N 3-amino-2-chloropropanoic acid Chemical compound NCC(Cl)C(O)=O XBQQNEFVNFNHDA-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- YTXXOZBXVGZYOR-UHFFFAOYSA-N 3-amino-2-bromopropanoic acid Chemical compound NCC(Br)C(O)=O YTXXOZBXVGZYOR-UHFFFAOYSA-N 0.000 description 2
- BKDFRSOQJDZWGS-UHFFFAOYSA-N 3-amino-2-bromopropanoic acid;hydrochloride Chemical compound Cl.NCC(Br)C(O)=O BKDFRSOQJDZWGS-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960004418 trolamine Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LCCNXMKLNXJTCO-UHFFFAOYSA-N 3-amino-2-chloropropanoic acid;sulfuric acid Chemical compound OS(O)(=O)=O.NCC(Cl)C(O)=O LCCNXMKLNXJTCO-UHFFFAOYSA-N 0.000 description 1
- GJMPSRSMBJLKKB-UHFFFAOYSA-N 3-methylphenylacetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1 GJMPSRSMBJLKKB-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- PACZJVHGWXZEGS-UHFFFAOYSA-N azanium;aziridine-2-carboxylate Chemical compound [NH4+].[O-]C(=O)C1CN1 PACZJVHGWXZEGS-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- WPJWIROQQFWMMK-UHFFFAOYSA-L beryllium dihydroxide Chemical compound [Be+2].[OH-].[OH-] WPJWIROQQFWMMK-UHFFFAOYSA-L 0.000 description 1
- 229910001865 beryllium hydroxide Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- HKRZTXMFJABEOO-UHFFFAOYSA-N ethyl 3-amino-2-chloropropanoate;hydrochloride Chemical compound Cl.CCOC(=O)C(Cl)CN HKRZTXMFJABEOO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- MENGZCGPSMYDEP-UHFFFAOYSA-M potassium;aziridine-2-carboxylate Chemical compound [K+].[O-]C(=O)C1CN1 MENGZCGPSMYDEP-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- MQHYSRLAEFWPQR-UHFFFAOYSA-N propan-2-yl aziridine-2-carboxylate Chemical compound CC(C)OC(=O)C1CN1 MQHYSRLAEFWPQR-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940117957 triethanolamine hydrochloride Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/02—Preparation by ring-closure
Definitions
- This invention relates to a novel process for producing an aziridine-2-carboxylic acid salt which is very useful as an intermediate for an alpha-amino acid, an agricultural chemical, a pharmaceutical, etc.
- an aziridine-2-carboxylic acid salt for example, for the production of sodium aziridine-2-carboxylate, there are known (1) a method which comprises neutralizing alpha-chloro-beta-alanine hydrochloride in water with an aqueous solution of sodium hydroxide, and while heating the neutralization product under reflux, adding a IN aqueous solution of sodium hydroxide dropwise so that the pH of the aqueous solution is maintained at 7 - 7.5 [K. D. Gundermann, Chem.
- Lithium aziridine-2-carboxylate is known to be produced by (3) a method which comprises treating alpha-chloro-beta-alanine ethyl ester hydrochloride with triethanolamine in ethanol to form-ethyl aziridine-2-carboxylate, and hydrolyzing the product with lithium hydroxide in a mixed solvent consisting of ethanol and water (K. D. Gundermann, Chem. Ber., 93, 1639 (1960)].
- the method (1) however, has the defect that it has to be operated while the concentration of the starting alpha-chloro-beta-alanine hydrochloride in the reaction system is maintained at as low as about 1% by weight.
- the methods (2) and (3) on the other hand, have the defect that synthesis of the aziridine-2-carboxylic acid ester is complex and the yield of the final product is low. Accordingly, none of these prior methods are entirely satisfactory in commercial practice.
- the present invention provides a process for producing an alkali metal salt, an alkaline earth metal salt or an ammonium salt of aziridine-2-carboxylic acid, which comprises treating an alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of said acid or ester with an alkali metal hydroxide, an alkaline earth metal hydroxide or aqueous ammonia in water or a water-containing organic solvent.
- the reaction conditions are mild, and the yield can be high.
- An aziridine-2-carboxylic acid salt is a very important intermediate for synthesis of amino acids and other compounds, as is demonstrated, for example, by the fact that treatment of lithium aziridine-2-carboxylate, in 15% sulfuric acid yields serine, a kind of alpha-amino acid.
- the process for producing aziridine-2-carboxylic acid salts in accordance with this invention has many advantages over the prior art in that it does not require pH control or heating and the reaction operation is simple, that an aziridine-2-carboxylic acid salt can be produced by using the reactant in a higher concentration than in the prior art in the reaction solution, and that the desired product can be obtained selectively without substantially forming by-products. Accordingly, the process of this invention is of very high utilitarian value in commercial practice.
- the starting alpha-halogeno-beta-aminopropionic acid or its mineral acid salt may, for example, include alpha-chloro-beta-aminopropionic acid, alpha-bromo-beta-aminopropionic acid, alpha-chloro-beta-aminopropionic acid hydrochloride or sulfate, and alpha-bromo-beta-aminopropionic acid hydrochloride or sulfate.
- alpha-halogeno-beta-aminopropionic acid ester or its mineral acid salt examples include alpha-chloro-beta-aminopropionic acid esters, alpha-bromo-beta-aminopropionic acid esters, alpha-chloro-beta-aminopropionic acid ester hydrochlorides and sulfates, and alpha-bromo-beta-aminopropionic acid ester hydrochlorides and sulfates.
- the ester used is an alkyl ester having 1 to 4 carbon atom in the alkyl moiety, and methyl esters, ethyl esters, isopropyl esters, tertiary butyl esters, etc. are used frequently.
- the mineral acid salt of an alpha-halogeno-beta-aminopropionic acid used as a starting material in the process of this invention is obtained by reacting an alpha, beta-dihalogenopropionitrile or an alpha-halogenoacrylo- nitrile with ammonia in water or in an organic solvent, and causing hydrogen chloride or sulfuric acid to act on the reaction mixture.
- the alpha-halogeno-beta-aminopropionic acid can be isolated by dissolving its mineral acid salt in the smallest amount of water, adding anhydrous ethanol, and neutralizing it [K. D. Gundermann, Chem. Ber., 91, 160 (1958)].
- the mineral acid salt of an alpha-halogeno-beta-aminopropionic acid ester for example, methyl alpha-chloro-beta-aminopropionate hydrochloride
- methyl alpha-chloro-beta-aminopropionate hydrochloride can be obtained by esterifying alpha-chloro-beta-aminopropionic acid hydrochloride in anhydrous methanol saturated with hydrochloric acid [K. D. Gundermann, Chem. Ber., 91, 160 (1958)].
- an alkali metal hydroxide, an alkaline earth metal hydroxide, or aqueous ammonia is used to perform the cyclization reaction of an alpha-halogeno-beta-aminopropinonic acid and the cyclization reaction and hydrolysis reaction of an alpha-halo ' geno- beta-aminopropionic acid ester.
- Specific examples of the alkali metal hydroxide or alkaline earth metal hydroxide are lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide.
- the alkali is used in an amount of at least 2 equivalents based on the starting material when the starting material is a free alpha-halogeno-beta-aminopropionic acid or an alpha-halogeno-beta-aminopropionic acid ester, and in an amount of at least 3 equivalents based on the starting material when the starting material is a mineral acid salt of the alpha-halogeno-beta-aminopropionic acid or the alpha-halogeno-beta-aminopropionic acid ester.
- the upper limit to the amount of the alkali is not specially limited. But it is not necessary to use it in large excess, and usually amounts of up to 5 equivalents are sufficient.
- the process of this invention is performed in water.or in a water-containing organic solvent.
- the reaction can be performed in an aqueous solution or in a solvent consisting of water and a water-miscible organic solvent.
- the water-miscible organic solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, tert.-butanol, Cellosolve and methyl Cellosolve, acetone, dioxane, tetrahydrofuran, N,N-dimethyl formamide, N,N-diethyl formamide and dimethyl sulfoxide.
- These organic solvents may be used as a mixture of two or more.
- the amount of water or the water-containing organic solvent is 3 to 200 times, preferably 5 to 100 times, the amount of the starting alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of said acid or ester.
- aqueous ammonia or the alkali or alkaline earth metal hydroxide as an aqueous solution or a solid is added with stirring to a solution of the alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of the acid or ester in water and/or a water-miscible organic solvent in a desired concentration.
- the alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of the acid or ester may be added to aqueous ammonia or an aqueous solution or suspension of the alkali or alkaline earth metal hydroxide.
- the reaction temperature is in the range of 0 to 100 °C, preferably 20 to 80°C.
- the reaction is carried out usually under atmospheric pressure, but if desired, it may be carried out under reduced or elevated pressure.
- the reaction time varies depending upon the reaction conditions. Usually, it comes to an end in 0.5 to 50 hours, particularly in 2.0 to 30 hours. The end point of the reaction can be rapidly and easily determined by thin-layer chromatography.
- the aziridine-2-carboxylic acid is obtained in the form of an alkali metal salt, an alkaline earth matal salt or an ammonium salt corresponding to the alkali metal hydroxide, alkaline earth metal hydroxide or aqueous ammonia used in the reaction.
- the organic solvent may be removed from the reaction product under reduced pressure to obtain the salt in the form of an aqueous solution.
- Lithium aziridine-2-carboxylate as a standard sample used in the Examples was synthesized in the following manner. Analysis by high-speed liquid chromatography in the Examples was performed under the following conditions.
- Example 3 was repeated except that 18.5 g of free alpha-chloro-beta-aminopropionic acid was used instead of the alpha-chloro-beta-propionic acid hydrochloride, and 21 g of sodium hydroxide was used instead of the lithium hydroxide.
- the yield of sodium aziridine-2-carboxylate formed was 89.6%.
- Example 6 was repeated except that 50 g of isopropyl alcohol was used instead of methanol, and 13 g of sodium hydroxide was used instead of lithium hydroxide. The yield of sodium aziridine-2-carboxylate formed was 90.5%.
- Example 8 was repeated except that 18.8 g of ethyl alpha-chrloro-beta-aminopropionate was used instead of the methyl alpha-chloro-beta-aminopropionate hydrochloride.
- the yield of sodium aziridine-2-carboxylate formed was 83.2%.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for producing an aziridine-2-carboxylic acid salt is provided which comprises treating an alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of said acid or ester with an alkali metal hydroxide, an alkaline earth metal hydroxide or aqueous ammonia in water or a water-containing organic solvent.
Description
- This invention relates to a novel process for producing an aziridine-2-carboxylic acid salt which is very useful as an intermediate for an alpha-amino acid, an agricultural chemical, a pharmaceutical, etc.
- Some methods for the production of an aziridine-2-carboxylic acid salt.have been known. For example, for the production of sodium aziridine-2-carboxylate, there are known (1) a method which comprises neutralizing alpha-chloro-beta-alanine hydrochloride in water with an aqueous solution of sodium hydroxide, and while heating the neutralization product under reflux, adding a IN aqueous solution of sodium hydroxide dropwise so that the pH of the aqueous solution is maintained at 7 - 7.5 [K. D. Gundermann, Chem. Ber., 93, 1640 (1960)], and (2) a method which comprises hydrolyzing isopropyl aziridine-2-carboxylate obtained by reaction between isopropyl alpha,beta-dibromopropio- nate and liquid ammonia, with sodium ethoxide in a mixed solvent consisting of ether, ethanol and water [E. Kyburz, Helv. Chim. Acta, 49, 368 (1966)]. Lithium aziridine-2-carboxylate is known to be produced by (3) a method which comprises treating alpha-chloro-beta-alanine ethyl ester hydrochloride with triethanolamine in ethanol to form-ethyl aziridine-2-carboxylate, and hydrolyzing the product with lithium hydroxide in a mixed solvent consisting of ethanol and water (K. D. Gundermann, Chem. Ber., 93, 1639 (1960)]. The method (1), however, has the defect that it has to be operated while the concentration of the starting alpha-chloro-beta-alanine hydrochloride in the reaction system is maintained at as low as about 1% by weight. The methods (2) and (3), on the other hand, have the defect that synthesis of the aziridine-2-carboxylic acid ester is complex and the yield of the final product is low. Accordingly, none of these prior methods are entirely satisfactory in commercial practice.
- It is an object of this invention therefore to provide a commercially advantageous process for producing an aziridine-2-carboxylic acid salt.
- The present invention provides a process for producing an alkali metal salt, an alkaline earth metal salt or an ammonium salt of aziridine-2-carboxylic acid, which comprises treating an alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of said acid or ester with an alkali metal hydroxide, an alkaline earth metal hydroxide or aqueous ammonia in water or a water-containing organic solvent. The reaction conditions are mild, and the yield can be high.
- An aziridine-2-carboxylic acid salt is a very important intermediate for synthesis of amino acids and other compounds, as is demonstrated, for example, by the fact that treatment of lithium aziridine-2-carboxylate, in 15% sulfuric acid yields serine, a kind of alpha-amino acid.
- The process for producing aziridine-2-carboxylic acid salts in accordance with this invention has many advantages over the prior art in that it does not require pH control or heating and the reaction operation is simple, that an aziridine-2-carboxylic acid salt can be produced by using the reactant in a higher concentration than in the prior art in the reaction solution, and that the desired product can be obtained selectively without substantially forming by-products. Accordingly, the process of this invention is of very high utilitarian value in commercial practice.
- In the process of this invention, the starting alpha-halogeno-beta-aminopropionic acid or its mineral acid salt may, for example, include alpha-chloro-beta-aminopropionic acid, alpha-bromo-beta-aminopropionic acid, alpha-chloro-beta-aminopropionic acid hydrochloride or sulfate, and alpha-bromo-beta-aminopropionic acid hydrochloride or sulfate. Examples of the alpha-halogeno-beta-aminopropionic acid ester or its mineral acid salt are alpha-chloro-beta-aminopropionic acid esters, alpha-bromo-beta-aminopropionic acid esters, alpha-chloro-beta-aminopropionic acid ester hydrochlorides and sulfates, and alpha-bromo-beta-aminopropionic acid ester hydrochlorides and sulfates. The ester used is an alkyl ester having 1 to 4 carbon atom in the alkyl moiety, and methyl esters, ethyl esters, isopropyl esters, tertiary butyl esters, etc. are used frequently.
- The mineral acid salt of an alpha-halogeno-beta-aminopropionic acid used as a starting material in the process of this invention is obtained by reacting an alpha, beta-dihalogenopropionitrile or an alpha-halogenoacrylo- nitrile with ammonia in water or in an organic solvent, and causing hydrogen chloride or sulfuric acid to act on the reaction mixture. The alpha-halogeno-beta-aminopropionic acid can be isolated by dissolving its mineral acid salt in the smallest amount of water, adding anhydrous ethanol, and neutralizing it [K. D. Gundermann, Chem. Ber., 91, 160 (1958)]. The mineral acid salt of an alpha-halogeno-beta-aminopropionic acid ester, for example, methyl alpha-chloro-beta-aminopropionate hydrochloride, can be obtained by esterifying alpha-chloro-beta-aminopropionic acid hydrochloride in anhydrous methanol saturated with hydrochloric acid [K. D. Gundermann, Chem. Ber., 91, 160 (1958)].
- In the process of this invention, an alkali metal hydroxide, an alkaline earth metal hydroxide, or aqueous ammonia is used to perform the cyclization reaction of an alpha-halogeno-beta-aminopropinonic acid and the cyclization reaction and hydrolysis reaction of an alpha-halo'geno- beta-aminopropionic acid ester. Specific examples of the alkali metal hydroxide or alkaline earth metal hydroxide are lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide. The alkali is used in an amount of at least 2 equivalents based on the starting material when the starting material is a free alpha-halogeno-beta-aminopropionic acid or an alpha-halogeno-beta-aminopropionic acid ester, and in an amount of at least 3 equivalents based on the starting material when the starting material is a mineral acid salt of the alpha-halogeno-beta-aminopropionic acid or the alpha-halogeno-beta-aminopropionic acid ester. The upper limit to the amount of the alkali is not specially limited. But it is not necessary to use it in large excess, and usually amounts of up to 5 equivalents are sufficient.
- The process of this invention is performed in water.or in a water-containing organic solvent. In other words, the reaction can be performed in an aqueous solution or in a solvent consisting of water and a water-miscible organic solvent. Examples of the water-miscible organic solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, tert.-butanol, Cellosolve and methyl Cellosolve, acetone, dioxane, tetrahydrofuran, N,N-dimethyl formamide, N,N-diethyl formamide and dimethyl sulfoxide. These organic solvents may be used as a mixture of two or more. When water and the organic solvent are used together, the ratio between them can be chosen as desired. The amount of water or the water-containing organic solvent is 3 to 200 times, preferably 5 to 100 times, the amount of the starting alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of said acid or ester.
- In performing the process of this invention, there is no particular restriction on the method and order of adding the starting material, the alkali and the reaction solvent. Usually, aqueous ammonia or the alkali or alkaline earth metal hydroxide as an aqueous solution or a solid is added with stirring to a solution of the alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of the acid or ester in water and/or a water-miscible organic solvent in a desired concentration. Alternatively, the alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of the acid or ester may be added to aqueous ammonia or an aqueous solution or suspension of the alkali or alkaline earth metal hydroxide.
- The reaction temperature is in the range of 0 to 100 °C, preferably 20 to 80°C. The reaction is carried out usually under atmospheric pressure, but if desired, it may be carried out under reduced or elevated pressure. The reaction time varies depending upon the reaction conditions. Usually, it comes to an end in 0.5 to 50 hours, particularly in 2.0 to 30 hours. The end point of the reaction can be rapidly and easily determined by thin-layer chromatography.
- In the process of this invention, the aziridine-2-carboxylic acid is obtained in the form of an alkali metal salt, an alkaline earth matal salt or an ammonium salt corresponding to the alkali metal hydroxide, alkaline earth metal hydroxide or aqueous ammonia used in the reaction. If desired, the organic solvent may be removed from the reaction product under reduced pressure to obtain the salt in the form of an aqueous solution.
- The following Examples illustrate the process of this invention more specifically.
- Lithium aziridine-2-carboxylate as a standard sample used in the Examples was synthesized in the following manner. Analysis by high-speed liquid chromatography in the Examples was performed under the following conditions.
- 10 g of ethyl alpha-chloro-beta-aminopropionate hydrochloride was dissolved in 100 ml of dehydrated ethanol, and 20 g of triethanolamine was added. With stirring, they were reacted at 60 to 70°C for 5 hours. The precipitated triethanolamine hydrochloride was separated by filtration, and washed with a small amount of ethanol. The filtrate and the washing were combined, and with cooling, 55 ml of-a IN aqueous solution of lithium hydroxide was gradually added. The mixture was allowed to stand for 24 hours in a cold dark place. The reaction mixture was then concentrated to dryness under reduced pressure. Then, 30 ml of benzene was added to the residue (syrupy material), and water was completely removed by azeotropic distillation. Then, 50 ml of hot ethanol was added, and the mixture was cooled to form a precipitate. 100 ml of ether was added to precipitate crystals fully. The prystals were separated by filtration, and washed with ether to afford 1.0 g of lithium aziridine-2-carboxylate.
- Melting point: 260 - 268°C (decomp.)
- Elemental analysis (%) for C3H4N02Li :
- The purity of the resulting lithium aziridine-2-carboxylate, determined by a proton NMR spectrum using dioxane as an internal standard (measuring solvent: D20, measuring temperature: room temperature), was 97%.
-
- Column: Shodex OH Pak B-804 (a product of Showa Denko K.K.)
- Detector: Differential refractometer RI-2 (a product of Nippon Bunseki Kogyo Co., Ltd.)
- Mobile phase: Aqueous solution of H3P04 (1 x 10-3 mole/liter)
- Flow rate: 1.3 ml/min.
- Measuring temperature: room temperature.
- Under these conditions, the retention time of aziridine-2-carboxylie acid was 16.5 to 16.8 minutes.
- 24 g of alpha-chloro-beta-aminopropionic acid hydrochloride was dissolved in 70 g of water. With stirring, a solution of 20 g of sodium hydroxide in 50 g of water was added dropwise to the resulting solution. Then, the reaction was performed at room temperature for 24 hours. The reaction mixture was analyzed by high-speed liquid chromatography. It was found that the yield of sodium aziridine-2-carboxylate was 93.5% based on the alpha-chloro-beta-aminopropionic acid hydrochloride.
- When the resulting reaction mixture was analyzed by proton NMR spectroscopy, a signal attributed to the methylene proton at δ=1.79 ppm (q., 2H) and a signal attributed to the methine proton at δ =2.35 ppm (q., 1H) were detected. This signal pattern was identical with that of lithium aziridine-2-carboxylate used as the standard sample.
- 17.3 g of alpha-chloro-beta-aminopropionic acid sulfate was dissolved in 100 g of water, and a solution of 18.0 g of potassium hydroxide in 60 g of water was added dropwise to the resulting solution with stirring. The reaction was performed at room temperature for 30 minutes. The reaction mixture was analyzed by high-speed liquid chromatography. The yield of potassium aziridine-2-carboxylate formed was 92.3%.
- 24 g of alpha-chloro-beta-aminopropionic acid hydrochloride was dissolved in 100 g of water, and a solution of 13 g of lithium hydroxide in 50 g of water was added dropwise to the resulting solution with stirring. The reaction mixture was then heated to 60°C, and reacted at 60 to 65°C for 4 hours. The reaction mixture was analyzed by high-speed liquid chromatography. The yield of lithium aziridine-2-carboxylate formed was 90.8%.
- Example 3 was repeated except that 18.5 g of free alpha-chloro-beta-aminopropionic acid was used instead of the alpha-chloro-beta-propionic acid hydrochloride, and 21 g of sodium hydroxide was used instead of the lithium hydroxide. The yield of sodium aziridine-2-carboxylate formed was 89.6%.
- 10.2 g of alpha-bromo-beta-aminopropionic acid hydrochloride was dissolved in 80 g of water, and a solution of 7 g of sodium hydroxide in 40 g of water was added dropwise to the resulting solution with stirring. The reaction was then performed at room temperature for 24 hours. The yield of sodium aziridine-2-carboxylate formed was 87.5%.
- 16.0 g of alpha-chloro-beta-aminopropionic acid hydrochloride was dissolved in a mixed solvent consisting of 90 g of water and 50 g of methanol, and an aqueous solution of 10.5 g of lithium hydroxide in 50 g of water was added dropwise to the resulting solution with stirring. Then, the reaction mixture was heated to 60°C, and reacted at 60 to 65°C for 8 hours. The methanol was distilled off under reduced pressure from the reaction mixture, and the residue was analyzed by high-speed liquid chromatography. The yield of lithium aziridine-2-carboxylate formed was 85.6%.
- Example 6 was repeated except that 50 g of isopropyl alcohol was used instead of methanol, and 13 g of sodium hydroxide was used instead of lithium hydroxide. The yield of sodium aziridine-2-carboxylate formed was 90.5%.
- 17.4 g of methyl alpha-chloro-beta-aminopropionate hydrochloride was dissolved in 140 g of water, and a solution of 13 g of sodium hydroxide in 60 g of water was added dropwise to the resulting solution with stirring. The mixture was then reacted at room temperature for 30 hours. The yield of sodium aziridine-2-carboxylate was 84.9%.
- Example 8 was repeated except that 18.8 g of ethyl alpha-chrloro-beta-aminopropionate was used instead of the methyl alpha-chloro-beta-aminopropionate hydrochloride. The yield of sodium aziridine-2-carboxylate formed was 83.2%.
- A solution of 19 g of alpha-chloro-beta-propionic acid hydrochloride in 50 g of water was added dropwise to 150 g of 8% aqueous ammonia, and they were reacted at room temperature for 48 hours. The yield of ammonium aziridine-2-carboxylate formed was 85.9%.
Claims (14)
1. A process for producing an aziridine-2-carboxylic acid salt, characterised in that it comprises treating an. alpha-halogeno-beta-aminopropionic acid, its ester or a mineral acid salt of said acid or ester with an alkali metal hydroxide, an alkaline earth metal hydroxide or aqueous ammonia in water or a water-containing organic solvent.
2. The process of claim 1 wherein the alpha-halogeno-beta-aminopropionic acid is alpha-chloro-beta-. aminopropionic acid or alpha-bromo-beta=aminopropionic acid.
3. The process of claim 1 wherein the alpha-halogeno-beta-aminopropionic acid ester is a methyl ester, ethyl ester, isopropyl ester or tert-butyl ester of alpha-chloro, or alpha-bromo-beta-aminopropLonic acid.
4. The process of any one of claims 1, 2 and 3 wherein the amount of the alkali metal hydroxide or alkaline earth metal hydroxide is 2 to 5 equivalents based on the alpha-halogeno-beta-aminopropionic acid or its ester.
5. The process of any one of claims 1, 2 and 3 wherein the mineral acid salt is a sulfate or hydrochloride.
6. The process of any one of claims 1 to 3 and 5 wherein the amount of the alkali metal hydroxide or - alkaline earth metal hydroxide is 3 to 5 equivalents based on the mineral acid salt of the alpha-halogeno-beta-aminopropionic acid ester.
7. The process of any one of the preceding claims wherein the alkali metal hydroxide is sodium hydroxide, potassium hydroxide or lithium hydroxide.
8. The process of any one of claims 1 to 6 wherein the alkaline earth metal hydroxide is calcium hydroxide.
9. The process of any one of the preceding claims wherein the water-containing organic solvent is a mixture of water and a water-miscible organic solvent.
10. The process of any one of claims 1 to 8 wherein the water-miscible organic solvent is methanol, ethanol, n-propanol, isopropanol, t-butanol, Cellosolve, methyl Cellosolve, acetone, dioxane, tetrahydrofuran, N,N-dimethyl formamide, N,N-diethyl formamide or dimethyl sulfoxide.
11. The process of any one of the preceding claims wherein the treatment is carried out at a temperature of 0 to 100°C.
12. A process for producing an aziridine-2-carboxylic acid salt, characterised in. that it comprises treating an alpha-halogeno-beta-aminopropionic acid ester or its mineral acid salt with an alkali metal hydroxide at 0 to 100°C in water or a water-containing organic solvent.'
13. The process of claim 12 wherein the amount of the alkali metal hydroxide is 2 to 5 equivalents based on the alpha-halogeno-beta-aminopropionic acid ester.
14. The process of claim 12 wherein the amount of the alkali metal hydroxide is 3 to 5 equivalents based on the mineral acid salt of the alpha-halogeno-beta-aminopropionic acid ester.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP163588/79 | 1979-12-18 | ||
| JP16358879A JPS6038382B2 (en) | 1979-12-18 | 1979-12-18 | Process for producing aziridine-2-carboxylate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0030870A1 true EP0030870A1 (en) | 1981-06-24 |
| EP0030870B1 EP0030870B1 (en) | 1985-03-20 |
Family
ID=15776761
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19800304566 Expired EP0030870B1 (en) | 1979-12-18 | 1980-12-17 | Process for producing solutions of aziridine-2-carboxylic acid salt |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0030870B1 (en) |
| JP (1) | JPS6038382B2 (en) |
| DE (1) | DE3070355D1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0191462A1 (en) * | 1985-02-13 | 1986-08-20 | Research Association For Utilization Of Light Oil | Purification of aziridine-2-carboxylic acid salts |
-
1979
- 1979-12-18 JP JP16358879A patent/JPS6038382B2/en not_active Expired
-
1980
- 1980-12-17 DE DE8080304566T patent/DE3070355D1/en not_active Expired
- 1980-12-17 EP EP19800304566 patent/EP0030870B1/en not_active Expired
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 89, No. 13, 25 September 1978 Columbus, Ohio, USA K. NAKAJIMA et al. "Studies on aziridine-2-carboxylic acid .I. Synthesis of the optically active L-aziridine-2-carboxylic acid and its derivatives" page 998, column 1, Abstract No. 110314a & Bull. Chem. Soc. Jpn, Vol. 51, No. 5, 1978, pages 1577 to 1578. * |
| CHEMISCHE BERICHTE, Vol. 93, No. 7, 1960 Weinheim/Bergstr. K.-D. GUNDERMANN et al. "Bildung, Ringspaltung und Isomerisierung von Athylenimin-carbonsaure-(2)-Derivaten" pages 1632 to 1643 * pages 1640 to 1641 * * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0191462A1 (en) * | 1985-02-13 | 1986-08-20 | Research Association For Utilization Of Light Oil | Purification of aziridine-2-carboxylic acid salts |
| US4935527A (en) * | 1985-02-13 | 1990-06-19 | Research Association For Utilization Of Light Oil | Production of aziridine-2-carboxylic acid salts |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3070355D1 (en) | 1985-04-25 |
| JPS5687556A (en) | 1981-07-16 |
| EP0030870B1 (en) | 1985-03-20 |
| JPS6038382B2 (en) | 1985-08-31 |
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